Human babesiosis is an infectious disease caused by intraerythrocytic

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e review article current concepts Human Babesiosis Edouard Vannier, Ph.D., and Peter J. Krause, M.D. Human babesiosis is an infectious disease caused by intraerythrocytic protozoa of the genus babesia. The disease is named after Victor Babes, the Hungarian pathologist and microbiologist who identified intraerythrocytic microorganisms as the cause of febrile hemoglobinuria in cattle in Five years later, Theobald Smith and Frederick L. Kilborne identified a tick as the vector for transmission of Babesia bigemina in Texas cattle. 2 This seminal observation established for the first time that an arthropod could transmit an infectious agent to a vertebrate host. The first documented human case of babesiosis was not recognized until about a half century later, when a splenectomized Croatian herdsman rapidly succumbed to an infection subsequently attributed to B. divergens. 3 The first case in an immunocompetent person was identified on Nantucket Island, off the coast of Massachusetts, in The causative agent was B. microti, and the vector was the Ixodes dammini tick (now referred to as I. scapularis). 5 Additional cases occurred on the island, and the disease became known as Nantucket fever. During the past decade, the incidence and geographic distribution of babesiosis have increased in the northeastern and upper midwestern regions of the United States. B. microti infection is almost as common as Lyme disease in some areas of southern New England, an observation that is consistent with the high prevalence of B. microti infected ticks in the region. 6-8 Babesiosis is now classified as a nationally notifiable disease and is recognized as an emerging health risk in several parts of the world. 9,10 From the Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston (E.V.); and the Department of Epidemiology of Microbial Diseases, Yale School of Public Health and Yale School of Medicine, New Haven, CT (P.J.K.). Address reprint requests to Dr. Krause at the Department of Epidemiology and Public Health, Yale School of Public Health and Yale School of Medicine, 60 College St., New Haven, CT , or at peter.krause@yale.edu. N Engl J Med 2012;366: Copyright 2012 Massachusetts Medical Society. Epidemiol o gy a nd Tr a nsmission More than 100 babesia species infect a wide array of wild and domestic animals, but only a few have been documented to infect humans. 5,10-12 The overwhelming majority of cases in the United States are caused by B. microti. Such cases occur in the Northeast and upper Midwest, primarily from May through October (Fig. 1). 10,12 The emergence of babesiosis in these regions has primarily been attributed to the expansion of the white-tailed deer population, encroachment of local communities on wildlife habitats, and greater awareness of the disease on the part of the public and physicians, although cases remain underreported. 6,33-35 A small number of cases caused by B. duncani and B. duncani type organisms have been identified on the Pacific Coast from northern California to Washington State Sporadic cases of infection with B. divergens like organisms have been documented in Kentucky, Missouri, and Washington State In Europe, most reported cases have been attributed to B. divergens, and a few have been caused by B. venatorum (formerly called EU1) and B. microti. 20,22-26 In Asia, B. microti like organisms have caused illness in Japan and Taiwan, whereas a new babesia agent (KO1 strain) has been identified in South Korea Sporadic cases of babesiosis have been reported in Africa, Australia, and South America. 15,20,21,27,32 n engl j med 366;25 nejm.org june 21,

2 T h e n e w e ngl a nd j o u r na l o f m e dic i n e I. persulcatus B. duncani B. divergens I. ricinus B. microti I. scapularis I. ovatus Figure 1. Geographic Areas Where Human Babesiosis and Ixodes Tick Vectors Are Endemic. Light colors denote areas where the ixodes tick vectors that transmit babesia are endemic but where babesiosis has yet to be documented in humans. 13 Dark colors designate areas where human babesiosis is either endemic (solid pattern) or sporadic, as defined by more than three tickborne cases reported in a country or state (stippled pattern). Isolated cases of locally acquired babesiosis are depicted by circles. In the United States, babesiosis caused by Babesia microti is endemic in the Northeast and the upper Midwest (dark-red areas), where it is transmitted by Ixodes scapularis. 5,6,12 Sporadic cases of babesiosis caused by B. duncani or B. duncani type organisms are reported along the northern Pacific Coast (orange stippled area) The tick vector is unknown, but I. pacificus is the primary candidate. 15 B. divergens like infections have been reported in Missouri, Kentucky, and Washington State (blue circles) In South America, symptomatic infections have been acquired in Brazil (not shown) and Colombia (open circle), but the etiologic agents were not molecularly characterized. 20,21 Three asymptomatic cases have been identified in Mexico (open circles). 15 In Europe, B. divergens is the primary agent of human babesiosis. 20,22,23 Cases are sporadic in France, Britain, and Ireland (dark-blue stippled areas), but isolated cases have been reported across the continent (blue circles). B. venatorum infections have been reported in Austria, Germany, and Italy (purple circles). 24,25 B. divergens and B. venatorum are phylogenetically related, and both are transmitted by I. ricinus. A single case of B. microti infection has been reported in Germany (red circle). 26 In Africa, cases caused by uncharacterized babesia species have been documented, including three in Egypt (open circles), one in Mozambique (not shown), and two in South Africa (not shown). 15,27 A case of B. divergens like infection was reported on the Canary Islands, off the coast of western Africa. 23 In Asia, B. microti like organisms caused two cases in Taiwan and one case in Japan (red circles) In the latter case, I. ovatus ticks infected with B. microti like organisms were found in the area, implicating this tick species as a vector of human babesiosis in Japan. I. persulcatus ticks also have been found to transmit B. microti like organisms to mammals but have not yet been established as a vector in human babesiosis. A case in South Korea was caused by the KO1 strain that is related to a species found in sheep (black circle). 31 Cases that were caused by uncharacterized babesia species have been documented in China and India (open circles). In Australia, a definitive case of B. microti infection has recently been identified (not shown). 32 Given the widespread distribution of the tick vectors that transmit babesia species in temperate latitudes, the prevalence of human babesiosis may be underestimated, although the endemic range of babesiosis may never reach the enzootic range of the tick species known to transmit babesia to humans. B. microti is primarily transmitted to people by I. scapularis. 34 Progression of I. scapularis through each of the three stages of its life cycle (larva, nymph, and adult) requires a blood meal from a vertebrate host (Fig. 2). The primary reservoir host for B. microti is the white-footed mouse (Peromyscus leucopus). 34 Although adult ticks may transmit B. microti, most cases result from exposure to nymphal ticks during the period from late spring through summer. 7,34 The tick vectors for transmission of B. duncani, B. duncani type, and B. divergens like parasites in the United States have yet to be conclusively identified. 20 In Europe, the sheep tick I. ricinus is the primary vector for transmission of B. divergens and B. venatorum. 20,23,36 Transplacental transmission of B. microti has been reported in a small number of cases. 37 A few babesia species are transmitted through transfusion of blood or blood products B. microti is the most common transfusion-transmitted pathogen reported to the Food and Drug Administration. 38,41,44 More than 150 cases of transfusion-transmitted babesiosis have been identified since the first case was reported in 1979, 45 and three quarters of these cases have occurred since Three cases have been caused by B. duncani. 46,47 The actual number of cases caused by B. microti and B. duncani is thought to be much greater because many are undetected or underreported. 41,43,46 Cases of transfusion-transmitted 2398 n engl j med 366;25 nejm.org june 21, 2012

3 current concepts Spring Summer Fall Babesia Larva Larva First year Adult Nymph Second year Figure 2. Transmission of Babesia microti by the Ixodes scapularis Tick. Adult female ticks lay eggs in the spring. 34 Larvae hatch in the early summer and become infected with B. microti as they take a blood meal from infected white-footed mice (Peromyscus leucopus) in late summer. White-footed mice are the primary reservoir host, but other small rodents may carry B. microti. Larvae molt into nymphs the following spring. When infected nymphs feed on mice or humans in late spring or early summer, these hosts may become infected. Humans are accidental hosts; most cases of babesia occur from late spring through summer. In the fall, nymphs molt into adults that feed on white-tailed deer (Odocoileus virginianus) but rarely on humans. White-tailed deer do not become infected with B. microti but amplify the tick population by providing a blood meal for adult ticks. The following spring, adult female ticks lay eggs that are free of B. microti (no transovarial transmission) and the cycle is repeated. B. microti are obligate parasites of erythrocytes and typically are visualized on a Giemsa-stained thin blood smear (inset). 12,20,23 The inset panels from left to right show a ring form with a nonstaining vacuole surrounded by cytoplasm (blue) and two small nuclei (purple), an amoeboid form, a tetrad (also referred to as a Maltese cross), and an extracellular form. babesiosis are often severe, since recipients of blood products frequently are immunocompromised or have coexisting medical conditions, and approximately a fifth of cases have been fatal. 46,48,49 Infections are reported throughout the year, but most occur from early summer through late fall. 46,49 About 10% of cases occur in nonendemic areas because persons may become infected at endemic sites and subsequently donate blood in nonendemic areas or because units of contaminated blood are exported to nonendemic areas ,46 Ph y l o gene tic Cl a ssific ation Babesia species belong to the phylum Apicomplexa, which includes the protozoan parasites causing malaria, toxoplasmosis, and cryptosporidiosis. 11 Babesia species that infect humans can be classified into four clades. 16,23,50 The first clade consists of B. microti, small parasites (<3 μm) that form a species complex in which nearly all human isolates belong to one subclade. 51,52 The second clade includes B. duncani and B. duncani type organisms, small babesia that are phylogenetically distinct n engl j med 366;25 nejm.org june 21,

4 T h e n e w e ngl a nd j o u r na l o f m e dic i n e from B. microti and are related to babesia of dogs and wildlife in the western United States. 15,16 The third clade includes B. divergens, a parasite of cattle, and B. venatorum, which infects roe deer. 23,24,36 These species are small but phylogenetically related to the large babesia ( 3 μm). The fourth clade consists of large babesia that infect ungulates and includes the KO1 strain. 23,31 LIFE C YCLE OF PATHO GEN B. microti undergo developmental changes within the tick vector and the reservoir host. 20,23,53 When larval ticks feed on infected mice in late summer (Fig. 2), gametocytes accumulate in the tick gut and differentiate into gametes. Gametes fuse to form zygotes that migrate across the gut epithelium into the hemolymph, where they mature into ookinetes. The ookinetes move to the salivary glands and become dormant sporoblasts. 53 As nymphal ticks feed in the early summer of the following year, several thousand sporozoites are delivered into the vertebrate host. Sporozoites attach to erythrocytes by docking onto glycosaminoglycans and sialoglycoproteins. 54,55 Once inside the erythrocytes, sporozoites mature into trophozoites, which eventually bud to form four merozoites. Egress of merozoites is accompanied by rupture of the host erythrocyte and invasion of other erythrocytes. Clinic a l M a nifes tations The clinical manifestations of babesiosis range from subclinical infection to fulminating disease resulting in death. 12 Most symptomatic patients become ill 1 to 4 weeks after the bite of a B. microti infected tick and 1 to 9 weeks (but up to 6 months in one reported case) after transfusion of contaminated blood products. 12,46 After a gradual onset of malaise and fatigue, fever usually develops, with a peak temperature that can be as high as 40.9 C (105.6 F). Chills and sweats are common and may be accompanied by headache, myalgia, anorexia, nonproductive cough, arthralgia, and nausea. 6,56-61 Occasional symptoms include vomiting, sore throat, abdominal pain, conjunctival injection, photophobia, weight loss, emotional lability, depression, and hyperesthesia. 12,56 On physical examination, fever is the most common sign. It may be accompanied by splenomegaly or occasionally by pharyngeal erythema, hepatomegaly, jaundice, or retinopathy with splinter hemorrhages and retinal infarcts. 12,56,57 Laboratory findings that are consistent with a mild-to-moderate hemolytic anemia include a low hematocrit, low hemoglobin level, low haptoglobin level, elevated reticulocyte count, and elevated lactate dehydrogenase level. 58,60,61 Thrombocytopenia is commonly observed. The illness usually lasts for 1 or 2 weeks, but fatigue may persist for months. 56,57,59,62 Asymptomatic parasitemia may persist for several months after standard therapy is initiated or for more than a year if the patient does not receive treatment. 56,62 Illness may relapse in severely immunocompromised patients despite 7 to 10 days of antimicrobial therapy and may persist for more than a year if not adequately treated The severity of babesiosis depends primarily on the immune status of the patient and on the babesia species causing the infection. About half of children and a quarter of previously healthy adults who are infected with B. microti have no symptoms. 6 Asymptomatic, mild, and moderate infections generally occur in people who are immunocompetent. 6,12,33 In contrast, severe B. microti illness requiring hospital admission is common among patients who have undergone splenectomy and those with cancer, human immunodeficiency virus infection, hemoglobinopathy, or chronic heart, lung, or liver disease. 49,60,63-66 Other groups at increased risk for severe disease include neonates, persons over the age of 50 years, patients receiving treatment with immunosuppressive drugs for cancer (e.g., rituximab) or undergoing organ transplantation, and those receiving anticytokine therapy (e.g., etanercept and infliximab). 25,37,58,60,65-69 Complications develop in approximately half of patients who are hospitalized with babesiosis. The acute respiratory distress syndrome and disseminated intravascular coagulopathy are the most common complications, but congestive heart failure, coma, liver failure, renal failure, or splenic rupture also may occur. 12,58,60 Fatality rates of 6 to 9% have been reported among hospitalized patients and up to 21% among those with immunosuppression. 58,60,65 Cases caused by B. duncani and B. duncani type organisms have ranged from asymptomatic to fatal. 14,15,47 Most reported cases of B. divergens infection are severe and occur in people who lack a spleen. 20,22 The fatality rate for B. divergens infection has dramatically declined since the introduction of aggres n engl j med 366;25 nejm.org june 21, 2012

5 current concepts sive treatment with a combination of antimicrobial agents and exchange transfusion. 20,22 All five reported cases of B. divergens like infection occurred in asplenic patients and were severe, resulting in the deaths of two patients ,23 Hos t R esis ta nce a nd Patho genesis Our understanding of host resistance against babesia species that infect humans is limited and based on human case studies and studies of babesiosis in natural vertebrate hosts and animal models. Splenectomy is a major risk factor for severe infection, regardless of the babesia species. 58,60,64-66,70 The spleen plays a central role in host defense by clearing infected erythrocytes from the bloodstream and mounting a protective immune response (Fig. 3) CD4+ T cells in mice with B. microti infection and natural killer cells in those with B. duncani infection produce interferon-γ, the prototypic type 1 helper T-cell (Th1) cytokine that promotes killing of intracellular pathogens by macrophages and enhances antibody production by B cells B cells are critical for resolution of B. microti infection in patients whose cellular immunity is impaired and most likely help to clear B. microti in immunocompetent patients. 25,65,69 The age-related decline in cellular immunity helps explain the severity of babesiosis in patients over the age of 50 years. In a mouse model of age-related susceptibility to B. microti parasitemia, the protection conferred by adoptive transfer of splenic immune cells is agedependent and genetically determined. 78 The pathogenesis of babesiosis is closely linked to the host response to infection and parasite-induced modifications in the erythrocyte membrane. In mild cases of babesiosis, inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α] and interleukin-6) and adhesion molecules (e.g., E-selectin, intracellular adhesion molecule 1 [ICAM-1], and vascular-cell adhesion molecule 1 [VCAM-1]) are up-regulated. 29 Excessive synthesis of cytokines, however, may result in severe babesiosis and associated complications. 72 Pulmonary inflammation in mice with B. duncani infection has been associated with excessive production of TNF-α and interferon-γ, and blockade of either cytokine prevents death. 77,79,80 Intravascular sequestration of leukocytes and infected erythrocytes may lead to obstruction of the microvasculature and tissue hypoxia. 72,81,82 Some babesia species export proteins to the surface of infected erythrocytes, resulting in the adherence of these erythrocytes to the vascular endothelium and in their delayed clearance by the spleen. 82 As with Plasmodium falciparum, the protein that is critical for cytoadherence of B. bovis infected erythrocytes is encoded by a variable multicopy gene family that contributes to immune evasion. 72,82 Cytoadherence of babesia-infected erythrocytes has yet to be documented in humans. Anemia that is caused by the rupture of erythrocytes during egress of babesia also contributes to pathogenesis, as do nonhemolytic mechanisms, such as the clearance of uninfected erythrocytes. 83 Di agnosis Babesiosis should be considered in any patient with an unexplained febrile illness who has resided in or traveled to an area where the infection is endemic within the previous 2 months or who has received a blood transfusion within the previous 6 months (Fig. 4). 12,39,43,46,84 The diagnosis requires a strong clinical suspicion because of the lack of an easily recognized clinical sign, such as the erythema migrans rash of Lyme disease. Since I. scapularis ticks can transmit B. microti, Borrelia burgdorferi, and Anaplasma phagocytophilum, babesiosis should be suspected in patients in whom Lyme disease or anaplasmosis has been diagnosed if more severe disease develops or if they have a poor response to standard antimicrobial therapy. 7,8,57,84,91 A definitive diagnosis is generally made by microscopical identification of babesia on thin blood smears with Giemsa or Wright staining (Fig. 2). 12,15,20,23 B. microti trophozoites appear as pleomorphic ring forms (round, oval, pear-shaped, or amoeboid) and are indistinguishable from B. duncani trophozoites. Although rare, tetrads of merozoites that are arranged in a cross-like pattern (a so-called Maltese cross) are pathognomonic for babesiosis caused by B. microti or B. duncani. 12,16 B. divergens and B. venatorum merozoites typically appear as paired pear-shaped forms but also rarely appear as tetrads in human red cells. 20,24 Although ring forms of babesia may resemble those of P. falciparum, malaria can be eliminated from consideration on the basis of a travel history and a careful review of blood smears. 12,15,20 Distinguishing features of babesia n engl j med 366;25 nejm.org june 21,

6 The n e w e ng l a n d j o u r na l of m e dic i n e Outer capsule Venous sinus Trabecula Cords Central arteriole T-cell zone B-cell follicle Spleen Marginal sinus Babesia-infected erythrocyte Marginal zone Macrophage Annular fiber Antibody-opsonized infected erythrocyte Marginal-zone Marginal macrophage sinus T cell Stress fibers Endothelial cell Erythrocyte Venule Collecting vein Venous sinus Red Pulp Marginalzone B cell Follicular B cell Central arteriole White Pulp Figure 3. The Splenic Response to Babesia Infection. The following composite model is based on studies of babesia infection in natural vertebrate hosts and animal models.12,71-77 The spleen is a heavily vascularized organ (top left panel) that consists of red-pulp zones and whitepulp zones surrounded by a trabecula and an outer capsule.71,74 A circulating erythrocyte travels through the spleen approximately once every 20 minutes. Erythrocytes enter the spleen by means of the trabecular artery and flow into central arteries and follicular arterioles to reach the marginal sinus of the white pulp. Once in the adjacent marginal zone, babesia-infected erythrocytes are ingested and destroyed by resident dendritic cells and macrophages.73 Marginal-zone macrophages do not express major histocompatibility complex (MHC) class II molecules but shed pathogen-degradation products that are picked up by marginal-zone B cells.71 Activated marginal-zone B cells and dendritic cells move to the T-cell zones, where they present antigen to T cells. Activated T cells migrate to the edge of the follicles and engage B cells, causing them to activate and eventually differentiate into antibody-secreting cells. Opsonization of babesia-infected erythrocytes by antibody promotes their clearance by phagocytes. Activated T cells also produce interferon-γ, the prototypic cytokine that helps macrophages kill ingested pathogens.75,76 Blood may bypass the white pulp and reach the red pulp directly.71,74 In the splenic cords of the red pulp, blood cells slowly flow between reticular fibers and are sensed by resident macrophages. Babesia-infected erythrocytes squeeze with difficulty through the apertures of the endothelium lining and are ingested by resident macrophages of the cords. Stress fibers that run longitudinally at the base of the endothelial-cell lining and connect to annular fibers can contract and loosen, thereby regulating the flow and size of erythrocytes that reach the venous sinuses. Blood cells that access the venous sinuses flow into venules and eventually reach the collecting vein n engl j med 366;25 nejm.org june 21, 2012

7 current concepts are pleomorphic ring forms, extracellular forms, the absence of identifiable gametocytes, and the absence of brown deposits (hemozoin). The level of parasitemia is generally between 1 and 10% but can be as high as 80%. 12,58,60,70 Because the parasitemia level is often less than 1% early in the course of illness, at least 300 microscopical fields should be reviewed (Fig. 4). Other laboratory tests are useful in establishing the diagnosis, especially when smears are negative. A polymerase-chain-reaction (PCR) assay is highly sensitive and specific for the detection of babesia DNA in blood, particularly with realtime technology. 85,86 The standard assay for the detection of babesia antibody is the indirect immunofluorescence assay IgM antibody usually is first detected 2 weeks after the onset of illness. 89 IgG titers often exceed 1:1024 during the acute phase of illness and decline to 1:64 or less within 8 to 12 months. 62,87 An immunoblot assay for detection of B. microti antibody is also available. 90 Assays for B. microti antibody do not detect B. duncani, B. divergens, or B. venatorum antibody. 14,15,20,43 When laboratory tests are inconclusive and infection is strongly suspected, a blood sample from the patient can be injected into a laboratory animal, such as a hamster. B. microti organisms usually appear in the blood of the inoculated animal within 2 to 4 weeks. 85 Tr e atmen t a nd Ou t come A combination of atovaquone and azithromycin is the treatment of choice for immunocompetent patients with mild-to-moderate babesiosis (Table 1). 59,92 One study showed that this combination was as effective as clindamycin and quinine in clearing parasitemia and resolving symptoms. 59 Only 15% of 41 patients receiving atovaquone and azithromycin had symptoms consistent with an adverse drug reaction, and only 1 patient (2%) had to discontinue the medications because of side effects. In contrast, three fourths of 18 patients receiving clindamycin and quinine had adverse drug reactions, and dose reduction or discontinuation of treatment was required in a third of these patients. Even patients with mild babesiosis should be treated with atovaquone and azithromycin because without treatment, the infection may not be cleared and severe disease may develop or the patients may inadvertently transmit the infection by donating blood. Treatment Negative Repeat testing if illness is severe Repeat blood smear Positive Antimicrobial therapy Patient at risk for Babesia microti infection Lives or travels where babesiosis is endemic Blood transfusion within 6 mo and Strong suspicion of babesiosis Giemsa or Wright staining of thin blood smear Negative If symptoms persist Negative Repeat testing if illness is severe Positive Antimicrobial therapy PCR or antibody assay Positive Consider antimicrobial therapy Figure 4. Algorithm for Diagnosis of Babesiosis Caused by Babesia microti. Diagnostic laboratory testing for babesiosis should be initiated only if there is a strong suspicion of infection and the patient is at risk for infection (because of residence in or travel to an area where babesiosis is endemic or receipt of a blood transfusion within the previous 6 months). 12,39,43,46,84 An example would be a patient living in an area where babesiosis is endemic, who is seen in the summertime for fever lasting more than 2 days with no apparent cause, and who removed an engorged tick within the past month. Babesiosis also should be considered in a patient with Lyme disease or human granulocytic anaplasmosis who reports symptoms that are more severe than usual or who has a poor response to standard antimicrobial therapy. 57,84 Laboratory testing is required for definitive diagnosis of babesiosis. Initial testing should consist of Giemsa or Wright staining of thin blood smears with oil immersion. 12,20,23 Babesia are often too small to be readily visualized on thick smears. 15 Automated hematology analyzers are not reliable in detecting babesia-infected erythrocytes. 15,20 Since the level of parasitemia may be low when the patient is first seen, additional thin blood smears may be required over the course of several days to detect the organism. Smears typically are repeated every 12 to 24 hours. When smears remain negative but the diagnosis is strongly suspected, a babesia-specific polymerase-chain-reaction (PCR) assay should be performed and if positive, antimicrobial therapy should be considered. 85,86 Detection of babesia antibody in serum may be helpful in making the diagnosis, but treatment that is based on positive serologic analysis alone should be avoided. Antibodies are detected by means of indirect immunofluorescence assay or immunoblotting High IgG titers ( 1:1024) are indicative of active or recent infection. The presence of IgM ( 1:64) without IgG antibody suggests either very recent infection or a false positive antibody reaction. Injection of the patient s blood into small rodents is useful when symptoms persist and other laboratory tests remain negative. 85 n engl j med 366;25 nejm.org june 21,

8 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Table 1. Antimicrobial Treatment of Human Babesiosis.* Treatment Atovaquone and azithromycin Atovaquone Azithromycin Clindamycin and quinine Clindamycin Oral Intravenous Quinine Dose Adult, 750 mg; pediatric, 20 mg/kg (maximum, 750 mg/dose) every 12 hr Adult, 500 mg on day 1 and 250 mg on subsequent days; pediatric, 10 mg/kg (maximum, 500 mg/dose) on day 1 and 5 mg/kg (maximum, 250 mg/dose) on subsequent days Adult, 600 mg every 8 hr; pediatric, 7 10 mg/kg (maximum, 600 mg/dose) every 6 8 hr Adult, mg every 6 hr; pediatric, 7 10 mg/kg (maximum, 600 mg/dose) every 6 8 hr Adult, 650 mg every 6 8 hr; pediatric, 8 mg/kg (maximum, 650 mg/dose) every 8 hr * All doses of antimicrobial therapy are administered for 7 to 10 days, except in patients with persistent relapsing infection, who receive such therapy for at least 6 weeks, including 2 weeks after babesia are no longer detected on a blood smear. Complete or partial exchange transfusion is recommended for babesiosis caused by Babesia divergens but should also be considered for any severe case of babesiosis caused by other babesia species, including B. microti and B. duncani. All antimicrobial agents are administered by mouth unless otherwise specified. For immunocompromised patients with babesiosis, successful outcomes have been reported with the use of atovaquone combined with higher doses of azithromycin ( mg per day). of asymptomatic carriers should be considered if parasites are detected for longer than 3 months. 92 The combination of clindamycin and quinine was the first successful antimicrobial regimen for the treatment of B. microti infection, 93 and intravenous clindamycin and oral quinine are still recommended for patients with severe babesial illness (Table 1). 92 When necessary, intravenous quinidine can be used instead of oral quinine but requires cardiac monitoring for possible prolongation of the QT interval. Partial or complete exchange transfusion of whole blood or packed red cells should be considered in patients with severe disease, particularly those infected with B. divergens. 12,20,23,45,94 Indications for such therapy include a high level of parasitemia ( 10%), clinically significant anemia, or renal, hepatic, or pulmonary compromise. 12,60,64,92 Severely immunocompromised patients may have persistent or relapsing babesiosis despite treatment with the standard course of 7 to 10 days of antimicrobial agents. 65 In such patients, a cure generally requires at least 6 weeks of antimicrobial therapy, including 2 weeks after babesia are no longer detected on blood smears. 65 High doses of azithromycin in combination with atovaquone have been used successfully in immunocompromised patients (Table 1). 95 Resistance to atovaquone and azithromycin occasionally develops during prolonged therapy (>4 weeks) that follows an initial, subcurative course of this combination. 66 Patients with babesiosis should be closely monitored during therapy. In most cases, symptoms abate within a day or two after antimicrobial therapy is initiated, and infection resolves within 3 months. 59,62,92 In severely ill patients, parasitemia should be monitored daily until it has decreased to a level of less than 5% and the patient s condition has improved. If symptoms recur, treatment should immediately resume, with close clinical follow-up. Pr e v en tion Preventive measures consist of personal, residential, and community approaches. 35,96-99 Personal protective measures include avoiding sites where ticks, mice, and deer thrive. It is especially important for persons at increased risk, such as asplenic or other immunocompromised persons who live in or travel to areas where babesiosis is endemic, to avoid deciduous forests and the edge between woodlands and open areas, where ticks may abound. 35,96,97 Persons who cannot avoid such areas should wear protective clothing, apply tick repellents containing permethrin or N,N-diethylmeta-toluamide (DEET) to clothing and repellents 2404 n engl j med 366;25 nejm.org june 21, 2012

9 current concepts containing DEET to skin, and examine themselves daily for ticks. 98 Landscape-management strategies, such as keeping grass mowed, removing leaf litter, using plantings that do not attract deer, and spraying areas of high tick density with acaricidal formulations, may help reduce the risk of tickborne infections. 97,99 The elimination of deer populations sharply reduces the risk of infection but is difficult to implement. 35 Public education about the risks and characteristic symptoms of tickborne diseases is an important part of these preventive measures. The current approach of questioning prospective blood donors about a history of babesiosis and indefinitely deferring those who have had the disease has not been effective in preventing transfusion-transmitted babesiosis. 39,41,43 Laboratory-based screening programs to identify prospective blood donors who are infected with babesia are being developed for use in areas where babesiosis is endemic. An interim analysis of the first such program showed that the combined use of an indirect immunofluorescence assay to detect B. microti antibody and a real-time PCR assay to detect B. microti DNA reduced the incidence of transfusion-transmitted babesiosis in neonates and children with sickle cell disease or thalassemia. 100 On the basis of the recent emergence of tickborne and transfusion-transmitted babesiosis, the development of a vaccine against human babesiosis should be considered. Supported by grants from the Gordon and Llura Gund Foundation (to Drs. Krause and Vannier) and the National Institutes of Health (R01 AG019781, to Dr. Vannier; and R21 AI088079, to Dr. Krause). No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Drs. Durland Fish, Timothy Lepore, and Kenneth Dardick for their critical review of a previous version of the manuscript; the late Dr. Andrew Spielman for his teaching and mentorship; Wendolyn Hill for providing artwork; and Rouette Hunter and Stephen Johnson for providing blood-smear micrographs. References 1. Babes V. Sur l hemoglobinurie bacterienne du boeuf. C R Acad Sci 1888;107: Smith T, Kilborne FL. Investigations into the nature, causation, and prevention of Texas or southern cattle fever. Department of Agriculture Bureau of Animal Industry bulletin no. 1. Washington, DC: Government Printing Office, 1893: Skrabalo Z, Deanovic Z. Piroplasmosis in man; report of a case. Doc Med Geogr Trop 1957;9: Western KA, Benson GD, Gleason NN, Healy GR, Schultz MG. Babesiosis in a Massachusetts resident. N Engl J Med 1970;283: Spielman A. Human babesiosis on Nantucket Island: transmission by nymphal Ixodes ticks. Am J Trop Med Hyg 1976; 25: Krause PJ, McKay K, Gadbaw J, et al. Increasing health burden of human babesiosis in endemic sites. Am J Trop Med Hyg 2003;68: Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from Ixodes ticks. Clin Microbiol Rev 2006;19: Tokarz R, Jain K, Bennett A, Briese T, Lipkin WI. Assessment of polymicrobial infections in ticks in New York State. Vector Borne Zoonotic Dis 2010;10: Jones KE, Patel NG, Levy MA, et al. Global trends in emerging infectious diseases. Nature 2008;451: Committee on Lyme Disease and Other Tick-Borne Diseases. The state of the science critical needs and gaps in understanding prevention, amelioration, and resolution of Lyme and other tick-borne diseases: the short-term and long-term outcomes: workshop report. Washington, DC: National Academies Press, Levine ND. Progress in taxonomy of the Apicomplexan protozoa. J Protozool 1988;35: Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am 2008;22: Brown RN, Lane RS, Dennis DT. Geographic distributions of tick-borne diseases and their vectors. In: Goodman J, Dennis DT, Sonenshine D, eds. Tick-borne diseases of humans. Washington, DC: American Society of Microbiology Press, 2005: Persing DH, Herwaldt BL, Glaser C, et al. Infection with a Babesia-like organism in northern California. N Engl J Med 1995;332: Kjemtrup AM, Conrad PA. Human babesiosis: an emerging tick-borne disease. Int J Parasitol 2000;30: Conrad PA, Kjemtrup AM, Carreno RA, et al. Description of Babesia duncani n.sp. (Apicomplexa: Babesiidae) from humans and its differentiation from other piroplasms. Int J Parasitol 2006;36: Herwaldt B, Persing DH, Précigout EA, et al. A fatal case of babesiosis in Missouri: identification of another piroplasm that infects humans. Ann Intern Med 1996;124: Beattie JF, Michelson ML, Holman PJ. Acute babesiosis caused by Babesia divergens in a resident of Kentucky. N Engl J Med 2002;347: Herwaldt BL, de Bruyn G, Pieniazek NJ, et al. Babesia divergens-like infection, Washington State. Emerg Infect Dis 2004; 10: Hunfeld KP, Hildebrandt A, Gray JS. Babesiosis: recent insights into an ancient disease. Int J Parasitol 2008;38: Ríos L, Alvarez G, Blair S. Serological and parasitological study and report of the first case of human babesiosis in Colombia. Rev Soc Bras Med Trop 2003;36: Gorenflot A, Moubri K, Precigout E, Carcy B, Schetters TP. Human babesiosis. Ann Trop Med Parasitol 1998;92: Gray J, Zintl A, Hildebrandt A, Hunfeld KP, Weiss L. Zoonotic babesiosis: overview of the disease and novel aspects of pathogen identity. Ticks Tick Borne Dis 2010;1: Herwaldt BL, Cacciò S, Gherlinzoni F, et al. Molecular characterization of a non- Babesia divergens organism causing zoonotic babesiosis in Europe. Emerg Infect Dis 2003;9: Häselbarth K, Tenter AM, Brade V, Krieger G, Hunfeld KP. First case of human babesiosis in Germany clinical presentation and molecular characterisation of the pathogen. Int J Med Microbiol 2007;297: Hildebrandt A, Hunfeld KP, Baier M, et al. First confirmed autochthonous case of human Babesia microti infection in Europe. Eur J Clin Microbiol Infect Dis 2007; 26: El-Bahnasawy MM, Khalil HH, Morsy TA. Babesiosis in an Egyptian boy acquired from pet dog, and a general review. J Egypt Soc Parasitol 2011;41: Shih CM, Liu LP, Chung WC, Ong SJ, n engl j med 366;25 nejm.org june 21,

10 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Wang CC. Human babesiosis in Taiwan: asymptomatic infection with a Babesia microti-like organism in a Taiwanese woman. J Clin Microbiol 1997;35: Shaio MF, Lin PR. A case study of cytokine profiles in acute human babesiosis. Am J Trop Med Hyg 1998;58: Wei Q, Tsuji M, Zamoto A, et al. Human babesiosis in Japan: isolation of Babesia microti-like parasites from an asymptomatic transfusion donor and from a rodent from an area where babesiosis is endemic. J Clin Microbiol 2001;39: Kim JY, Cho SH, Joo HN, et al. First case of human babesiosis in Korea: detection and characterization of a novel type of Babesia sp. (KO1) similar to ovine babesia. J Clin Microbiol 2007;45: Senanayake SN, Paparini A, Latimer M, et al. First report of human babesiosis in Australia. Med J Aust 2012;196: Ruebush TK II, Juranek DD, Chisholm ES, Snow PC, Healy GR, Sulzer AJ. Human babesiosis on Nantucket Island: evidence for self-limited and subclinical infections. N Engl J Med 1977;297: Spielman A, Wilson ML, Levine JF, Piesman J. Ecology of Ixodes damminiborne human babesiosis and Lyme disease. Annu Rev Entomol 1985;30: Hayes EB, Piesman J. How can we prevent Lyme disease? N Engl J Med 2003; 348: Bonnet S, Jouglin M, L Hostis M, Chauvin A. Babesia sp. EU1 from roe deer and transmission within Ixodes ricinus. Emerg Infect Dis 2007;13: Fox LM, Wingerter S, Ahmed A, et al. Neonatal babesiosis: case report and review of the literature. Pediatr Infect Dis J 2006;25: Leiby DA. Transfusion-associated babesiosis: shouldn t we be ticked off? Ann Intern Med 2011;155: Gubernot DM, Nakhasi HL, Mied PA, Asher DM, Epstein JS, Kumar S. Transfusion-transmitted babesiosis in the United States: summary of a workshop. Transfusion 2009;49: Asad S, Sweeney J, Mermel LA. Transfusion-transmitted babesiosis in Rhode Island. Transfusion 2009;49: Young C, Krause PJ. The problem of transfusion-transmitted babesiosis. Transfusion 2009;49: Perkins HA, Busch MP. Transfusionassociated infections: 50 years of relentless challenges and remarkable progress. Transfusion 2010;50: Leiby DA. Transfusion-transmitted Babesia spp.: bull s-eye on Babesia microti. Clin Microbiol Rev 2011;24: Biological product and hematopoietic cell therapy/product (HCT/P) deviation report annual summary for Fiscal Year Silver Spring, MD: Food and Drug Administration, 2009 ( SafetyAvailability/ReportaProblem/ BiologicalProductDeviations/ucm htm). 45. Jacoby GA, Hunt JV, Kosinski KS, et al. Treatment of transfusion-transmitted babesiosis by exchange transfusion. N Engl J Med 1980;303: Herwaldt BL, Linden JV, Bosserman E, Young C, Olkowska D, Wilson M. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med 2011;155: Bloch EM, Herwaldt BL, Leiby DA, et al. The third described case of transfusiontransmitted Babesia duncani. Transfusion 2011 December 13 (Epub ahead of print). 48. Gubernot DM, Lucey CT, Lee KC, Conley GB, Holness LG, Wise RP. Babesia infection through blood transfusions: reports received by the US Food and Drug Administration, Clin Infect Dis 2009;48: Tonnetti L, Eder AF, Dy B, et al. Transfusion-transmitted Babesia microti identified through hemovigilance. Transfusion 2009;49: Telford SR III, Goethert HK. Emerging tick-borne infections: rediscovered and better characterized, or truly new? Parasitology 2004;129:Suppl:S301-S Goethert HK, Telford SR III. What is Babesia microti? Parasitology 2003;127: Fujisawa K, Nakajima R, Jinnai M, et al. Intron sequences from the CCT7 gene exhibit diverse evolutionary histories among the four lineages within the Babesia microti-group, a genetically related species complex that includes human pathogens. Jpn J Infect Dis 2011;64: Rudzinska MA, Spielman A, Lewengrub S, Piesman J, Karakashian S. The sequence of developmental events of Babesia microti in the gut of Ixodes dammini. Protistologica (Paris) 1984;20: Yokoyama N, Okamura M, Igarashi I. Erythrocyte invasion by Babesia parasites: current advances in the elucidation of the molecular interactions between the protozoan ligands and host receptors in the invasion stage. Vet Parasitol 2006;138: Lobo CA, Rodriguez M, Cursino-Santos JR. Babesia and red cell invasion. Curr Opin Hematol 2012;19: Ruebush TK II, Cassaday PB, Marsh HJ, et al. Human babesiosis on Nantucket Island: clinical features. Ann Intern Med 1977;86: Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis: evidence for increased severity and duration of illness. JAMA 1996;275: White DJ, Talarico J, Chang HG, Birkhead GS, Heimberger T, Morse DL. Human babesiosis in New York State: review of 139 hospitalized cases and analysis of prognostic factors. Arch Intern Med 1998; 158: Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000;343: Hatcher JC, Greenberg PD, Antique J, Jimenez-Lucho VE. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis 2001;32: Joseph JT, Roy SS, Shams N, et al. Babesiosis in Lower Hudson Valley, New York, USA. Emerg Infect Dis 2011;17: Krause PJ, Spielman A, Telford SR III, et al. Persistent parasitemia after acute babesiosis. N Engl J Med 1998;339: Falagas ME, Klempner MS. Babesiosis in patients with AIDS: a chronic infection presenting as fever of unknown origin. Clin Infect Dis 1996;22: Stowell CP, Gelfand JA, Shepard JA, Kratz A. Case Records of the Massachusetts General Hospital (Case ). N Engl J Med 2007;356: Krause PJ, Gewurz BE, Hill D, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 2008;46: Wormser GP, Prasad A, Neuhaus E, et al. Emergence of resistance to azithromycin-atovaquone in immunocompromised patients with Babesia microti infection. Clin Infect Dis 2010;50: Taiwo B, Lee C, Venkat D, Tambar S, Sutton SH. Can tumor necrosis factor alpha blockade predispose to severe babesiosis? Arthritis Rheum 2007;57: Cullen G, Sands BE, Yajnik V. Babesiosis in a patient on infliximab for Crohn s disease. Inflamm Bowel Dis 2010;16: Lubin AS, Snydman DR, Miller KB. Persistent babesiosis in a stem cell transplant recipient. Leuk Res 2011;35(6):e77- e Meldrum SC, Birkhead GS, White DJ, Benach JL, Morse DL. Human babesiosis in New York State: an epidemiological description of 136 cases. Clin Infect Dis 1992;15: Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol 2005;5: Krause PJ, Daily J, Telford SR, Vannier E, Lantos P, Spielman A. Shared features in the pathobiology of babesiosis and malaria. Trends Parasitol 2007;23: Froberg MK, Dannen D, Bernier N, Shieh WJ, Guarner J, Zaki S. Case report: spontaneous splenic rupture during acute parasitemia of Babesia microti. Ann Clin Lab Sci 2008;38: n engl j med 366;25 nejm.org june 21, 2012

11 current concepts 74. Buffet PA, Safeukui I, Deplaine G, et al. The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. Blood 2011;117: Igarashi I, Waki S, Ito M, Omata Y, Saito A, Suzuki N. Role of CD4 + T cells in the control of primary infection with Babesia microti in mice. J Protozool Res 1994; 4: Clawson ML, Paciorkowski N, Rajan TV, et al. Cellular immunity, but not gamma interferon, is essential for resolution of Babesia microti infection in BALB/c mice. Infect Immun 2002;70: Aguilar-Delfin I, Wettstein PJ, Persing DH. Resistance to acute babesiosis is associated with interleukin-12- and gamma interferon-mediated responses and requires macrophages and natural killer cells. Infect Immun 2003;71: Vannier E, Borggraefe I, Telford SR III, et al. Age-associated decline in resistance to Babesia microti is genetically determined. J Infect Dis 2004;189: Hemmer RM, Ferrick DA, Conrad PA. Role of T cells and cytokines in fatal and resolving experimental babesiosis: protection in TNFRp55 / mice infected with the human Babesia WA1 parasite. J Parasitol 2000;86: Hemmer RM, Ferrick DA, Conrad PA. Up-regulation of tumor necrosis factoralpha and interferon-gamma expression in the spleen and lungs of mice infected with the human Babesia isolate WA1. Parasitol Res 2000;86: Dao AH, Eberhard ML. Pathology of acute fatal babesiosis in hamsters experimentally infected with the WA-1 strain of Babesia. Lab Invest 1996;74: Allred DR. Babesiosis: persistence in the face of adversity. Trends Parasitol 2003; 19: Otsuka Y, Yamasaki M, Yamato O, Maede Y. The effect of macrophages on the erythrocyte oxidative damage and the pathogenesis of anemia in Babesia gibsoniinfected dogs with low parasitemia. J Vet Med Sci 2002;64: Krause PJ, McKay K, Thompson CA, et al. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002;34: Krause PJ, Telford S III, Spielman A, et al. Comparison of PCR with blood smear and inoculation of small animals for diagnosis of Babesia microti parasitemia. J Clin Microbiol 1996;34: Teal AE, Habura A, Ennis J, Keithly JS, Madison-Antenucci S. A new real-time PCR assay for improved detection of the parasite Babesia microti. J Clin Microbiol 2012;50: Ruebush TK II, Chisholm ES, Sulzer AJ, Healy GR. Development and persistence of antibody in persons infected with Babesia microti. Am J Trop Med Hyg 1981; 30: Krause PJ, Telford SR III, Ryan R, et al. Diagnosis of babesiosis: evaluation of a serologic test for the detection of Babesia microti antibody. J Infect Dis 1994;169: Krause PJ, Ryan R, Telford S III, Persing D, Spielman A. Efficacy of immunoglobulin M serodiagnostic test for rapid diagnosis of acute babesiosis. J Clin Microbiol 1996;34: Ryan R, Krause PJ, Radolf J, et al. Diagnosis of babesiosis using an immunoblot serologic test. Clin Diagn Lab Immunol 2001;8: Des Vignes F, Fish D. Transmission of the agent of human granulocytic ehrlichiosis by host-seeking Ixodus scapularis (Acari:Ixodidae) in southern New York State. J Med Entomol 1997;34: Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43: [Erratum, Clin Infect Dis 2007;45:941.] 93. Wittner M, Rowin KS, Tanowitz HB, et al. Successful chemotherapy of transfusion babesiosis. Ann Intern Med 1982;96: Spaete J, Patrozou E, Rich JD, Sweeney JD. Red cell exchange transfusion for babesiosis in Rhode Island. J Clin Apher 2009;24: Weiss LM, Wittner M, Tanowitz HB. The treatment of babesiosis. N Engl J Med 2001;344: Desforges JF, Quimby F. Babesia abroad. N Engl J Med 1976;295: Stafford KC III. Tick management handbook: an integrated guide for homeowners, pest control operators, and public health officials for the prevention of tick-associated disease. New Haven: Connecticut Agricultural Experimental Station, 2007: Vázquez M, Muehlenbein C, Cartter M, Hayes EB, Ertel S, Shapiro ED. Effectiveness of personal protective measures to prevent Lyme disease. Emerg Infect Dis 2008;14: Fish D, Childs JE. Community-based prevention of Lyme disease and other tickborne diseases through topical application of acaricide to white-tailed deer: background and rationale. Vector Borne Zoonotic Dis 2009;9: Young C, Chawla A, Berardi V, Padbury J, Skowron G, Krause PJ. Preventing transfusion-transmitted babesiosis: preliminary experience of the first laboratory-based blood donor screening program. Transfusion 2012 March 27 (Epub ahead of print). 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